We are currently characterizing the insulin resistance associated with obesity in the Pima Indians. Adipose cell size, which has long been associated with insulin resistance and obesity, is a focus of these studies. Insulin action is measured both in adipocytes in vitro and in vivo. Studies in adults indicate that cell size is distributed bimodally and that cell size is limited by some maximum size. The average cell size and obesity is related to insulin action. Larger adipocytes have smaller responses of glucose transport to insulin than smaller adipocytes, and glucose transport and antilipolysis are less sensitive to insulin and obese individuals versus lean individuals. Lipolysis is greatly increased with increasing adipose cell size. The capacity for decreased glucose transport in adipocytes is not affected by cell size or obesity. Similar findings have been found with the euglycemic clamp where the capacity (2000 MuU/ml clamp) is not well correlated with obesity while the sensitivity (estimated from the 100 MuU/ml clamp) is affected by obesity. Also free fatty acids levels rise in obesity. Since the in vivo glucose uptake results are reflection of insulin in muscle we have assumed that the similarities between the in vivo and in vitro studies are due similarities between muscle and fat. A major question is whether cell size changes are really important in the generation of insulin resistance associated with obesity or whether it is simply a consequence of some other factor common to fat and muscle. In an attempt to look at individuals with similar levels of obesity, but potentially different adipose cell sizes and levels of insulin resistance, we are currently studying Pima Indian children of similar obesity with family histories of NIDDM and those without. Preliminary results suggest that children of a mother diabetic during pregnancy have very large adipose cell sizes relative to children of normal causasians of similar age and obesity.